Sex hormone dysregulation after traumatic brain injury: interactions with sleep disturbances and seizure susceptibility

TL;DR

This review explores how traumatic brain injury disrupts sex hormones, which may worsen sleep issues and seizures, offering new insights into recovery and treatment.

Contribution

The paper highlights sex hormone dysregulation as an underrecognized pathway linking TBI to sleep and seizure outcomes.

Findings

TBI alters estrogen, progesterone, and testosterone levels, affecting neuroinflammation and neuronal survival.

Hormonal changes after TBI are linked to increased seizure susceptibility and disrupted sleep patterns.

Early detection of hormonal imbalances could guide new therapeutic strategies for TBI recovery.

Abstract

Each year, approximately 2.9 million people in the United States sustain a traumatic brain injury (TBI), many of whom go on to experience chronic secondary complications such as post-traumatic epilepsy (PTE) and sleep–wake disturbances. These outcomes arise from complex secondary injury processes, including neuroinflammation, oxidative stress, and disruptions in neuroendocrine signaling. While inflammatory and excitotoxic mechanisms have been extensively studied, growing evidence highlights sex hormone dysregulation—particularly involving estrogen, progesterone, and testosterone—as an important yet underrecognized contributor to post-TBI physiology. Clinical and preclinical studies indicate that TBI can alter systemic and brain-derived hormone levels, influencing neuroinflammation, glial activation, neuronal survival, and synaptic plasticity. These hormone-related changes have been associated with altered seizure susceptibility and disrupted sleep architecture, suggesting that sex hormone dysregulation may represent one interacting pathway influencing both outcomes. Additionally, the bidirectional relationship between epilepsy and sleep—where seizures disrupt sleep architecture and sleep loss increases cortical excitability—may further compound vulnerability after TBI. Given the heterogeneity of injury mechanisms and hormonal responses across individuals, these relationships remain incompletely understood but biologically plausible. This narrative review examines how TBI-related alterations in estrogen, progesterone, and testosterone may intersect with sleep regulation and seizure susceptibility. We summarize their physiological roles in the brain, evaluate how post-injury disruptions may shape chronic outcomes, and highlight how early identification of hormonal abnormalities could inform future research on therapeutic strategies. By addressing this understudied interface between endocrine, neural, and behavioral dysfunction, we aim to advance understanding of modifiable pathways that may contribute to long-term morbidity after TBI.

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